This application claims the benefit under 35 U.S.C. §119(e) of prior U.S. Provisional Patent Application No. 61/222,220, filed Jul. 1, 2009, which is incorporated in its entirety by reference herein.
The present invention relates to methods for preventing various immune responses, and more particularly, relates to methods for preventing autoimmune disease.
Signals delivered through stimulatory and inhibitory co-receptors regulate lymphocyte activation in collaboration with primary antigen-receptor signals. Stimulatory co-receptors include CD28 and inducible T-cell costimulator (ICOS), whereas inhibitory co-receptors include cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and B and T lymphocyte attenuator (BTLA) (1, 2). Accumulating evidence indicates that the balance between stimulatory and inhibitory co-signals is crucial not only for the effective immune responses to pathogens but also for the maintenance of self-tolerance (1, 2). BTLA has originally been identified as an inhibitory co-receptor selectively expressed on Th1 cells and B cells (3). Thereafter, flow cytometric analyses using monoclonal antibodies against BTLA have revealed that BTLA is expressed on certain lymphocyte subsets including γδ T cells and regulatory T cells as well as on some antigen-presenting cells (APCs) such as macrophages and dendritic cells (DCs) (4, 5). BTLA has also been reported to be expressed at low levels on NK cells (4, 6). More recently, it has been shown that a TNFR family member herpesvirus entry mediator (HVEM) is a ligand for BTLA (5, 7, 8) and that the ligation of BTLA with HVEM transduces inhibitory co-signals (5).
While B and T lymphocyte attenuator (BTLA) was originally identified as an inhibitory co-receptor selectively expressed on Th1 cells and B cells, recent studies have revealed that BTLA is expressed on a variety of cells including macrophages, dendritic cells, and NK cells and modulates their functions. However, the role of BTLA in the regulation of NKT cell function remains unknown.
In vivo function of BTLA has recently been addressed using BTLA-deficient (BTLA−/−) mice. Initially, the present inventors found that the sensitivity to experimental autoimmune encephalomyelitis (EAE) as well as T cell-dependent antibody responses is increased in BTLA−/− mice (3). It has also been reported that BTLA−/− mice exhibit a rapid rejection of partially MHC-mismatched cardiac allograft (9), persistent allergic airway inflammation following antigen challenge (10, 11), and an acceleration of experimental colitis (12). These findings indicate that BTLA is crucial for dampening immune responses mediated by T cells. Moreover, the present inventors have found that aged BTLA−/− mice spontaneously develop autoimmune hepatitis-like disease with an increase of NKT cells in the liver (13), suggesting that BTLA may prevent autoimmune hepatitis through the inhibition of NKT cell function.
NKT are characterized by co-expression of T cell markers such as T cell receptor (TCR) and NK cell markers such as NK1.1 (14). In mice, the majority of NKT cells expresses an invariant Vα14 TCR, which is essential for their development (14), and recognizes a specific ligand, α-galactosylceramide (α-GalCer), presented on CD1d molecules (14, 15). NKT cells rapidly produce both IL-4 and IFN-γ upon activation (15, 16) and play a crucial role in various immune responses, including anti-tumor immunity, allergic reaction, and autoimmune diseases (14). While the roles of stimulatory co-receptors in NKT cell function have been addressed (17, 18), the role of inhibitory co-receptors including BTLA in NKT cell function remains largely unknown.